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Novel Agents in FL: Unmet Needs and Potential Uses

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Friday, Feb 02, 2018



Transcript: 

Ian W. Flinn, MD, PhD: There are now a whole bunch of other drugs that are being tested in follicular lymphoma, and they have some promising activity. There’s a range of drugs, including ibrutinib and venetoclax. Anas, what’s your take on some of these?

Anas Younes, MD: I think there are a lot of agents being tested in the multiple-relapse indolent lymphomas with modest activity. That brings us back to the issue that’s being discussed: We need to identify biomarkers to select these patients. As single agents, none of them will probably make it as a drug that will be approved based on single-agent activity, with few exceptions. I think the exception is probably the EZH2 inhibitor, tazemetostat, which actually uses a biomarker, which is the EZH2 mutations. Interestingly, if you treat patients with EZH2 mutations in follicular lymphoma, you get a 92% response rate. It’s a small number of patients, because these mutations are not very highly prevalent. Even in the EZH2 wild-type population, we can see some responses, but with huge differences between the responses. We could see responses better in the EZH2-mutant large cell lymphomas compared with wild-type. I think that’s beautiful evidence that if you select patients based on a biologic biomarker, you can take a drug that [gives] you a 20% or 30% response rate and make it a 90% response rate.

Venetoclax has activity. We’ve been very disappointed because it targets the very mechanism that defines follicular lymphoma, BCL2, but the response rate was only 20% or 25%. So, we need to find out who the correct patients are. But again, it may not be good as a single agent. Maybe these are good for combinations. So, we need to find out what the optimal partners are for combinations moving forward.

Ian W. Flinn, MD, PhD: In many ways, it actually doesn’t surprise me at all. I remember when the first venetoclax data came out in CLL, there were these tremendous response rates. I guess I was disappointed in follicular lymphoma that it wasn’t higher, but with the mechanism of action, I would have thought that they really did need to be combined with other agents for ultimate potency.

Anas Younes, MD: I think that’s the way it will be in the future, with a combination strategy.

Ian W. Flinn, MD, PhD: Yes. It’s going to be a challenge, right?

Loretta J. Nastoupil, MD: Right. Just to build off of your comment, I think we shouldn’t just combine things based on our prior experience and what works in lymphoma, particularly follicular lymphoma. If we can be a little bit more strategic or rational about the combinations, we can focus a little bit more on some of the preclinical data or the biomarkers that drive the combination. We get a little bit frustrated when we just do these 2-, 3-, 4-drug combinations because, “Well, they’ve worked before, let’s just build on the backbone,” because we have to consider cost, both in terms of financial cost but also toxicity to the patient. Although combinations are probably going to be the most promising, we do need to mindful of not just opening a study because it’s a CD20, it’s a BTK, or it’s a BCL2 inhibitor. They should all work if we combine them.

Peter Martin, MD, MS: There’s an interesting report with venetoclax. I agree 100% with everything that has been said. Ideally, combinations should be rational, not random. The interesting thing is that venetoclax is one of the few drugs where it is actually a rational combination with chemotherapy, right? And still, it wasn’t impressive when it was combined with bendamustine and rituximab in follicular lymphoma. We saw those data last year at ASH. When it’s combined rationally, it’s still a little bit disappointing. But there probably is a better combination out there.

Anas Younes, MD: Right. But the combination does mean with chemotherapy, right? We need to figure out what mediates resistance. It’s still an absolutely perfect target, BCL2. Everybody knows that BCL2 is important for survival. But in the presence of a target, although it’s required, it may not be sufficient to predict response. We need to figure out what the mechanisms are. There are a lot of indications. MCL1 can compensate, and that’s why everybody is interested in MCL1-targeted agents. Whether they can combine both within safety is a different issue, but we need to look at other mechanisms that can mediate resistance to BCL2 inhibitors.

Grzegorz S. Nowakowski, MD: I couldn’t agree more with what you said. I think we assume that translocation drives follicular lymphoma with the BCL2 translocation. But it appears that venetoclax is quite active in the diseases that have overexpression of BCL2, like CLL or mantle cell lymphoma. It is possible that in the setting of translocation, the mechanism is slightly different and that’s why the response rate is not as high as we’re hoping for.

Ian W. Flinn, MD, PhD: I also worry from a drug development standpoint in general. How are we going to do some of these things, such as looking for these very small subpopulations, like the EZH2 mutants? Right now, I think most centers don’t standardly do a next-generation panel on their patients with follicular lymphoma. If they did, they’d find a very small group. Talk about expensive. When you start developing new therapies for smaller and smaller subgroups of this, it’s a challenge.

Anas Younes, MD: It is a challenge. The good news is that there is now a movement to accept these assays that are useful for preclinical practice. The FDA just approved 2 assays within the last week: one from Foundation Medicine and one from Memorial Sloan Kettering. So, this is happening now. It’s applied to clinical practice. But I agree with you. When you have a biomarker, a genetic alteration that is at low frequency and druggable, I think the next approach is to combine more than 1 that feed into 1 pathway and probably not just 1 drug, but 2 drugs, to enlarge the bucket or population within the biomarker.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: There are now a whole bunch of other drugs that are being tested in follicular lymphoma, and they have some promising activity. There’s a range of drugs, including ibrutinib and venetoclax. Anas, what’s your take on some of these?

Anas Younes, MD: I think there are a lot of agents being tested in the multiple-relapse indolent lymphomas with modest activity. That brings us back to the issue that’s being discussed: We need to identify biomarkers to select these patients. As single agents, none of them will probably make it as a drug that will be approved based on single-agent activity, with few exceptions. I think the exception is probably the EZH2 inhibitor, tazemetostat, which actually uses a biomarker, which is the EZH2 mutations. Interestingly, if you treat patients with EZH2 mutations in follicular lymphoma, you get a 92% response rate. It’s a small number of patients, because these mutations are not very highly prevalent. Even in the EZH2 wild-type population, we can see some responses, but with huge differences between the responses. We could see responses better in the EZH2-mutant large cell lymphomas compared with wild-type. I think that’s beautiful evidence that if you select patients based on a biologic biomarker, you can take a drug that [gives] you a 20% or 30% response rate and make it a 90% response rate.

Venetoclax has activity. We’ve been very disappointed because it targets the very mechanism that defines follicular lymphoma, BCL2, but the response rate was only 20% or 25%. So, we need to find out who the correct patients are. But again, it may not be good as a single agent. Maybe these are good for combinations. So, we need to find out what the optimal partners are for combinations moving forward.

Ian W. Flinn, MD, PhD: In many ways, it actually doesn’t surprise me at all. I remember when the first venetoclax data came out in CLL, there were these tremendous response rates. I guess I was disappointed in follicular lymphoma that it wasn’t higher, but with the mechanism of action, I would have thought that they really did need to be combined with other agents for ultimate potency.

Anas Younes, MD: I think that’s the way it will be in the future, with a combination strategy.

Ian W. Flinn, MD, PhD: Yes. It’s going to be a challenge, right?

Loretta J. Nastoupil, MD: Right. Just to build off of your comment, I think we shouldn’t just combine things based on our prior experience and what works in lymphoma, particularly follicular lymphoma. If we can be a little bit more strategic or rational about the combinations, we can focus a little bit more on some of the preclinical data or the biomarkers that drive the combination. We get a little bit frustrated when we just do these 2-, 3-, 4-drug combinations because, “Well, they’ve worked before, let’s just build on the backbone,” because we have to consider cost, both in terms of financial cost but also toxicity to the patient. Although combinations are probably going to be the most promising, we do need to mindful of not just opening a study because it’s a CD20, it’s a BTK, or it’s a BCL2 inhibitor. They should all work if we combine them.

Peter Martin, MD, MS: There’s an interesting report with venetoclax. I agree 100% with everything that has been said. Ideally, combinations should be rational, not random. The interesting thing is that venetoclax is one of the few drugs where it is actually a rational combination with chemotherapy, right? And still, it wasn’t impressive when it was combined with bendamustine and rituximab in follicular lymphoma. We saw those data last year at ASH. When it’s combined rationally, it’s still a little bit disappointing. But there probably is a better combination out there.

Anas Younes, MD: Right. But the combination does mean with chemotherapy, right? We need to figure out what mediates resistance. It’s still an absolutely perfect target, BCL2. Everybody knows that BCL2 is important for survival. But in the presence of a target, although it’s required, it may not be sufficient to predict response. We need to figure out what the mechanisms are. There are a lot of indications. MCL1 can compensate, and that’s why everybody is interested in MCL1-targeted agents. Whether they can combine both within safety is a different issue, but we need to look at other mechanisms that can mediate resistance to BCL2 inhibitors.

Grzegorz S. Nowakowski, MD: I couldn’t agree more with what you said. I think we assume that translocation drives follicular lymphoma with the BCL2 translocation. But it appears that venetoclax is quite active in the diseases that have overexpression of BCL2, like CLL or mantle cell lymphoma. It is possible that in the setting of translocation, the mechanism is slightly different and that’s why the response rate is not as high as we’re hoping for.

Ian W. Flinn, MD, PhD: I also worry from a drug development standpoint in general. How are we going to do some of these things, such as looking for these very small subpopulations, like the EZH2 mutants? Right now, I think most centers don’t standardly do a next-generation panel on their patients with follicular lymphoma. If they did, they’d find a very small group. Talk about expensive. When you start developing new therapies for smaller and smaller subgroups of this, it’s a challenge.

Anas Younes, MD: It is a challenge. The good news is that there is now a movement to accept these assays that are useful for preclinical practice. The FDA just approved 2 assays within the last week: one from Foundation Medicine and one from Memorial Sloan Kettering. So, this is happening now. It’s applied to clinical practice. But I agree with you. When you have a biomarker, a genetic alteration that is at low frequency and druggable, I think the next approach is to combine more than 1 that feed into 1 pathway and probably not just 1 drug, but 2 drugs, to enlarge the bucket or population within the biomarker.

Transcript Edited for Clarity 
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